Document Detail

Initiation and execution of lipotoxic ER stress in pancreatic beta-cells.
MedLine Citation:
PMID:  18559892     Owner:  NLM     Status:  MEDLINE    
Free fatty acids (FFA) cause apoptosis of pancreatic beta-cells and might contribute to beta-cell loss in type 2 diabetes via the induction of endoplasmic reticulum (ER) stress. We studied here the molecular mechanisms implicated in FFA-induced ER stress initiation and apoptosis in INS-1E cells, FACS-purified primary beta-cells and human islets exposed to oleate and/or palmitate. Treatment with saturated and/or unsaturated FFA led to differential ER stress signaling. Palmitate induced more apoptosis and markedly activated the IRE1, PERK and ATF6 pathways, owing to a sustained depletion of ER Ca(2+) stores, whereas the unsaturated FFA oleate led to milder PERK and IRE1 activation and comparable ATF6 signaling. Non-metabolizable methyl-FFA analogs induced neither ER stress nor beta-cell apoptosis. The FFA-induced ER stress response was not modified by high glucose concentrations, suggesting that ER stress in primary beta-cells is primarily lipotoxic, and not glucolipotoxic. Palmitate, but not oleate, activated JNK. JNK inhibitors reduced palmitate-mediated AP-1 activation and apoptosis. Blocking the transcription factor CHOP delayed palmitate-induced beta-cell apoptosis. In conclusion, saturated FFA induce ER stress via ER Ca(2+) depletion. The IRE1 and resulting JNK activation contribute to beta-cell apoptosis. PERK activation by palmitate also contributes to beta-cell apoptosis via CHOP.
Daniel A Cunha; Paul Hekerman; Laurence Ladrière; Angie Bazarra-Castro; Fernanda Ortis; Marion C Wakeham; Fabrice Moore; Joanne Rasschaert; Alessandra K Cardozo; Elisa Bellomo; Lutgart Overbergh; Chantal Mathieu; Roberto Lupi; Tsonwin Hai; Andre Herchuelz; Piero Marchetti; Guy A Rutter; Décio L Eizirik; Miriam Cnop
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-06-17
Journal Detail:
Title:  Journal of cell science     Volume:  121     ISSN:  0021-9533     ISO Abbreviation:  J. Cell. Sci.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-07-03     Completed Date:  2008-10-07     Revised Date:  2013-06-11    
Medline Journal Info:
Nlm Unique ID:  0052457     Medline TA:  J Cell Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  2308-18     Citation Subset:  IM    
Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium.
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MeSH Terms
Activating Transcription Factor 3 / metabolism
Activating Transcription Factor 6 / metabolism
Apoptosis / drug effects
Calcium / metabolism
Endoplasmic Reticulum / drug effects*,  enzymology,  pathology*
Fatty Acids, Nonesterified / metabolism,  toxicity*
Glucose / toxicity
Insulin-Secreting Cells / drug effects*,  enzymology,  pathology*
JNK Mitogen-Activated Protein Kinases / metabolism
Membrane Proteins / metabolism
Middle Aged
Protein-Serine-Threonine Kinases / metabolism
Rats, Wistar
Signal Transduction / drug effects
Transcription Factor CHOP / metabolism
eIF-2 Kinase / metabolism
Grant Support
067081/Z/02/Z//Wellcome Trust; 081958/Z/07/Z//Wellcome Trust; R01 CA118306/CA/NCI NIH HHS; R01 DK059605/DK/NIDDK NIH HHS; R01 DK071962-02/DK/NIDDK NIH HHS; //Medical Research Council
Reg. No./Substance:
0/ATF3 protein, human; 0/Activating Transcription Factor 3; 0/Activating Transcription Factor 6; 0/Atf3 protein, rat; 0/Fatty Acids, Nonesterified; 0/Membrane Proteins; 147336-12-7/Transcription Factor CHOP; 50-99-7/Glucose; 7440-70-2/Calcium; EC 2.7.1.-/Ern2 protein, rat; EC 2.7.10.-/PERK kinase; EC Kinases; EC Kinase; EC Mitogen-Activated Protein Kinases

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